Streif Werner, Escuriola Ettingshausen C, Linde R, Kropshofer G, Zimmerhackl L-B, Kreuz W
Dept. of Paediatrics, Medical University Innsbruck, 6020 Innsbruck, Austria.
Hamostaseologie. 2009 May;29(2):151-4.
The development of neutralizing alloantibodies (inhibitors) to factor VIII (FVIII) is one of the most serious complications in the treatment of haemophiliacs. Inhibitors occur in approximately 20 to 30% of previously untreated patients (PUPs), predominantly children, with severe haemophilia A within the first 50 exposure days (ED). Immune tolerance induction (ITI) leads to complete elimination of the inhibitor in up to 80% of the patients and offers the possibility to restore regular FVIII prophylaxis. However, patients with high titre inhibitors, in whom standard ITI fails, usually impose with high morbidity and mortality and therefore prompting physicians to alternate therapy regimens. Rituximab, an anti-CD 20 monoclonal antibody has been successfully used in children and adults for the management of B-cell mediated disorders. We report on the use of a new protocol including rituximab in two adolescents with severe haemophilia A and high titre inhibitors, severe bleeding tendency and high clotting factor consumption after failing standard ITI. Both patients received a concomitant treatment with FVIII according to the Bonn protocol, cyclosporine A and immunoglobulin. Treatment with rituximab resulted in a temporary B-cell depletion leading to the disappearance of the inhibitor. FVIII recovery and half-life turned towards normal ranges. In patient 1 the inhibitor reappeared 14 months after the last rituximab administration. In patient 2 complete immune tolerance could be achieved for 60 months. Bleeding frequency diminished significantly and clinical joint status improved in both patients. In patient 1 the treatment course was complicated by aspergillosis and hepatitis B infection.
Rituximab may be favourable for patients with congenital haemophilia, high-titre inhibitors and a severe clinical course in whom standard ITI has failed. Prospective studies are required to determine safety, efficacy and predictors of success.
产生针对凝血因子VIII（FVIII）的中和性同种抗体（抑制剂）是血友病患者治疗中最严重的并发症之一。在既往未治疗的患者（PUPs）中，约20%至30%会出现抑制剂，主要是儿童，在最初50个暴露日（ED）内患有严重A型血友病。免疫耐受诱导（ITI）可使高达80%的患者完全消除抑制剂，并有可能恢复常规FVIII预防治疗。然而，标准ITI治疗失败的高滴度抑制剂患者通常具有较高的发病率和死亡率，因此促使医生更换治疗方案。利妥昔单抗，一种抗CD20单克隆抗体，已成功用于儿童和成人治疗B细胞介导的疾病。我们报告了一种新方案，该方案包括在两名患有严重A型血友病、高滴度抑制剂、严重出血倾向且标准ITI治疗失败后凝血因子消耗高的青少年中使用利妥昔单抗。两名患者均根据波恩方案接受了FVIII、环孢素A和免疫球蛋白的联合治疗。利妥昔单抗治疗导致B细胞暂时耗竭，从而使抑制剂消失。FVIII恢复和半衰期恢复至正常范围。在患者1中，最后一次利妥昔单抗给药14个月后抑制剂再次出现。在患者2中，可实现60个月的完全免疫耐受。两名患者的出血频率均显著降低，临床关节状况得到改善。在患者1中，治疗过程因曲霉菌病和乙型肝炎感染而复杂化。
对于先天性血友病、高滴度抑制剂且标准ITI治疗失败的严重临床病程患者，利妥昔单抗可能是有益的。需要进行前瞻性研究以确定安全性、疗效和成功的预测因素。
